PROJECT SUMMARY The illnesses caused by Streptococcus pneumoniae's transition from carriage to disease results in a mortality rate between approximately 3-10% in adults and 12-25% in elderly patients in the United States. Furthermore, pneumococcal disease devastates resource-poor countries, causing an estimated 476,000 (~32% of vaccine-preventable deaths in children below age five) to succumb to pneumococcal infection annually. The most effective vaccines, polysaccharide protein conjugates, require a complicated process of collecting polysaccharide antigens from pneumococci serotypes and conjugating them to a protein adjuvant. Abcombi Biosciences has developed a pneumococcal vaccine using liposomal encapsulation of polysaccharides (LEPS), which has demonstrated conjugate-like efficacy against 70+ serotypes of S. pneumoniae via animal challenge models and opsonophagocytosis activity (OPA). To our knowledge, this represents the broadest protection demonstrated by a conjugate-like vaccine to date using an OPA assay, which is recognized as the gold standard for clinical efficacy against S. pneumoniae. In the proposed Phase I application, Abcombi Biosciences outlines a plan to overcome the risk for potential negative side effects associated with the LEPS vaccine's current formulation. Briefly, the inclusion one pneumococcal virulent protein (GlpO) and his-tags creates the potential for off-target effects. In this approach, serum from GlpO- vaccinated mice will be evaluated for cross-reactivity against a representative set commensal microflora using immunofluorescence and OPA assays. In addition, a portfolio of protein-to-liposome attachment strategies will be immunologically characterized by quantifying antibody titers, antibody class shifting, and OPA activity. Upon completing these studies, we will consult with our CMC and regulatory advisors to select the most promising candidate for long-term manufacturing. This candidate will then be subjected to a comprehensive immunological and toxicological assessment in preparation for IND-enabling studies. This work will serve as the basis for process optimization studies that will be conducted in a future Phase II study.